Mucosal addressin cell adhesion molecule (MAdCAM) is a member of the immunoglobulin superfamily of cell adhesion receptors. It is one of the adhesion molecules involved in the recruitment of lymphocytes to tissues when required, by means of interacting with an integrin molecule on the surface of the lymphocytes.
It has been shown that antibodies that inhibit binding of MAdCAM to its integrin binding partner, α4β7, for example anti-MAdCAM antibodies (e.g. MECA-367; U.S. Pat. No. 5,403,919, U.S. Pat. No. 5,538,724) or anti-α4β7 antibodies (e.g. Act-1; U.S. Pat. No. 6,551,593 or humanised Act-1, also called MLN02, described in WO 01/78779), can inhibit leukocyte extravasation into inflamed intestine, and can therefore be beneficial in the treatment of inflammatory bowel disease.
Anti-MAdCAM antibodies such as MECA-367, however, are not therapeutically useful in human patients; MECA-367 binds mouse MAdCAM, and does not show much affinity for the human MAdCAM molecule. In addition, being a rat antibody, it will lead to an immune response in human patients and therefore not be suitable for therapeutic use. Mouse monoclonal antibodies, directed against human MAdCAM have been described (WO 96/24673), but these are also likely to be immunogenic in humans. Recently, therapeutically useful, fully human anti-human MAdCAM antibodies with exquisite specificity and affinity to human and primate MAdCAM have been developed and disclosed in WO2005/067620.
It is known that even fully human antibodies can still lead to an immune response in some patients, which is likely to be due to sequences in the variable region of the antibody. The antibodies of the present invention are modifications of the human anti-MAdCAM antibodies disclosed in WO2005/067620, which are likely to be even less prone to any immunogenicity problems in human patients.